It is known that supercritical carbon dioxide has been used as a reaction medium in hydrogenation reactions.

However, disadvantageously, the solubility of reagents and/or catalysts in the fluid may be relatively low and, furthermore, in some cases the carbon dioxide itself may be inserted into metal-hydride bonds of catalysts resulting in the formation of formate complexes.

It is an object of the present invention to address problems associated with the use of carbon dioxide in hydrogenation reactions.

According to a first aspect of the present invention, there is provided a process for hydrogenating one or more functional groups in a compound, the process comprising contacting said compound with a hydrogen source in the presence of a reaction solvent selected from a C14 fluorinated hydrocarbon or a C14 hydrofluorocarbon ether.

A said hydrofluorocarbon ether preferably comprises one or more carbon, fluorine, hydrogen and oxygen atoms only. It may include up to 10, preferably up to 8, more preferably, up to 6, fluorine atoms. It preferably includes at least 2, more preferably at least 3 fluorine atoms. It is preferably aliphatic and/or saturated. An example of a

hydrofluorocarbon ether is 1,1, 1,2, 2-pentafluorethyl methyl ether.

Preferably, however, the process is carried out in the presence of a said C14 fluorinated hydrocarbon, rather than in the presence of a said hydrofluorocarbon ether.

Said Cl4 fluorinated hydrocarbon is preferably non- chlorinated. Preferably, it comprises one or more carbon, fluorine and hydrogen atoms only. Preferably, said fluorinated hydrocarbon is a Ci-s, more preferably a Cl-2, fluorinated hydrocarbon. Especially preferred is a C2 fluorinated hydrocarbon.

Said fluorinated hydrocarbon may include up to 10, preferably up to 8, more preferably up to 6, especially up to 4, fluorine atoms. Preferably, said fluorinated hydrocarbon includes at least 2, more preferably at least 3, fluorine atoms.

Said fluorinated hydrocarbon is preferably aliphatic. It is preferably saturated.

Said fluorinated hydrocarbon may have a boiling point at atmospheric pressure of less than 20°C, preferably less than 10°C, more preferably less than 0°C, especially less than-10°C. The boiling point may be greater than-90°C, preferably greater than-70°C, more preferably greater than-50°C.

Preferred fluorinated hydrocarbons are difluoromethane, tetrafluoroethane, especially 1,1, 1,2-tetrafluoroethane, and heptafluoropropane, especially 1, 1,1, 2,3, 3,3,-

heptafluoropropane. Of the aforesaid, tetrafluoroethane, especially 1, 1,1, 2-tetrafluoroethane, is preferred.

The reaction solvent may comprise a said C14 fluorinated hydrocarbon or a said d Cl-4 hydrofluorocarbon ether together with a modifier (or co-solvent) which is suitably arranged to affect the properties of the reaction solvent. Said modifier may be another Cl_4 fluorinated hydrocarbon or C14 hydrofluorocarbon ether of the type described or a material of a different type.

A said modifier may be selected from: a C2-6 hydrocarbon such as an alkane or cycloalkane with alkanes such as ethane, n-propane, i-propane, n-butane and i-butane being especially preferred; and hydrocarbon ethers, particularly dialkylethers such as dimethylether, methylethylether and diethyl ether. In other embodiments, said modifier may be polar, for example having a dielectric constant, at 20°C, of greater than 5. Such modifier may be selected from: amides, especially N, N'-dialkylamides and alkylamides, with dimethylformamide and formamide being preferred; sulphoxides, especially dialkyl sulphoxides, with dimethylsulphoxide being preferred; alcohols, especially aliphatic alcohols for example alkanols, with methanol, ethanol, 1-propanol and 2-propanol being preferred ; ketones, especially aliphatic ketones, for example dialkyl ketones, with acetone being especially preferred; organic acids, especially carboxylic acids with formic acid and acetic acid being preferred; carboxylic acid derivatives, for example anhydrides, with acetic anhydride being preferred; cyanide derivatives, for example hydrogen cyanide and alkyl cyanides, with methyl cyanide and liquefied anhydrous hydrogen cyanide being preferred;

ammonia; sulphur containing molecules including sulphur dioxide, hydrogen sulphide and carbon disulphide; inorganic acids for example hydrogen halides with liquefied anhydrous hydrogen fluoride, chloride, bromide and iodide being preferred; nitro derivatives, for example nitroalkanes and nitroaryl compounds, with nitromethane and nitrobenzene being especially preferred.

In the process, the pressure during contact between said hydrogen source and reaction solvent may be at least 50 bar. It is preferably at least 60 bar and, more preferably, at least 70 bar. The pressure may be in the range 50-280 bar. In the process, the temperature during said contact may be at least 50°C, preferably at least 70°C. The temperature is preferably less than 150°C, more preferably less than 125°C.

Said Cl_4 fluorinated hydrocarbon or said Ci-4 hydrofluorocarbon ether selected for use in the process is preferably a supercritical fluid. The process is preferably carried out under conditions at which said fluorinated hydrocarbon or said hydrofluorocarbon ether is near or more preferably is in a supercritical state. The term supercritical state refers to a state wherein a fluid is at or above its critical pressure and critical temperature.

Preferably, said reaction solvent used in the process is near to or more preferably is in a supercritical state during the process. Thus, if a modifier is used in the reaction solvent as descried above, said modifier is preferably a supercritical fluid. Examples of such modifiers include supercritical carbon dioxide, nitrous

oxide, sulphur hexafluoride, xenon, chlorofluoromethane and ethane. An especially preferred modifier is carbon dioxide. Up to 60wt% of said modifier may be used.

Preferably, however, 50wt% or less, more preferably 25wt% or less, especially 10 wt% or less of modifier may be used. However, in preferred embodiments, no modifier is used in said reaction solvent. Suitably, therefore said reaction solvent consists essentially of a single solvent of a type described.

The process of the first aspect is suitably carried out in the presence of a catalyst. Said catalyst is preferably a transition metal catalyst. Wilkinson's catalyst is an example of a suitable catalyst but other catalysts able to catalyse hydrogenation reactions may be selected.

Advantageously, the reaction solvent is able to solubilise relatively large amounts of catalyst and, accordingly, the efficiency of the process may be improved compared to a case wherein a solvent is used which is only poorly able to solubilise a selected catalyst.

Thus, whilst the process could involve heterogenous catalysis, preferably a homogenous solution of catalyst in said reaction solvent is used in the process. Thus, said process of the first aspect is preferably a homogenous hydrogenation reaction.

The process of said first aspect may be used to hydrogenate a wide range of hydrogenatable functional groups. A functional group which is hydrogenated in the process may be: an alkene (including a cyclic alkene), cyclic alkane, lactone, anhydride, amide, lactam, Schiffs base, aldehyde, ketone, alcohol, nitro, hydroxylamine,

nitrile, oxime, imine, azine, hydrazone, aniline, azide, cyanate, isocyanate, thiocyanate, isothiocyanate, diazonium, azo, nitroso, phenol, ether, furan, epoxide, hydroperoxide, peroxide, ozonide, arene, saturated or unsaturated heterocycle, halide, acid halide, acetal, ketal, and a selenium or sulfur containing compound.

Preferably, the functional group is an alkene group.

Preferably, therefore, said compound hydrogenated in the process is an alkene.

The reference to said hydrogen source includes hydrogen and its isotopes. Preferably, however, said source is of hydrogen, rather than isotopes thereof.

Said hydrogen source may comprise a source of hydrogen gas which may be supplied under pressure to an apparatus in which said hydrogenation is taking place. Alternatively, a transfer hydrogenation process may be carried out using an organic hydrogen source for example Et3N/HCOOH.

In the process of the first aspect, the hydrogenation may take place in a first receptacle. Suitably, a catalyst is provided in the first receptacle and this is contacted with a source of hydrogen which is fed to the receptacle.

Then, the reaction solvent is preferably supplied to the first receptacle, suitably under pressure and suitably so that the reaction solvent pressurizes the first receptacle at the desired pressure. Preferably, the reaction solvent is arranged to flush the compound to be hydrogenated into the first receptacle during the solvent's passage to the first receptacle. When the process involves homogenous catalysis, the reaction solvent preferably dissolves the

catalyst in the first receptacle. Thereafter, the hydrogenation reaction may commence.

According to a second aspect of the invention, there is provided a method of separating components of a reaction mixture wherein said components include a catalyst, a product of a hydrogenation reaction and a reaction solvent, and wherein said catalyst and said product have different solubilities in said reaction solvent, the method comprising: with the reaction mixture under a first pressure in a first receptacle, reducing the pressure in said first receptacle so that a component of the reaction mixture which is least soluble in the reaction solvent predominantly separates from the reaction mixture.

The invention of the second aspect is preferably used after the process of the first aspect. Thus, there may be provided a process comprising: (i) contacting a compound, having one or more hydrogenatable functional groups, with a hydrogen source in the presence of a reaction solvent as described according to said first aspect and a catalyst in order to hydrogenate one or more said hydrogenatable groups; and (ii) reducing the pressure in the vicinity of the reaction mixture so that a component of the reaction mixture which is least soluble in the reaction solvent predominantly separates from the reaction mixture.

In said second aspect, preferably said first receptacle is connected to a second receptacle and the arrangement is such that reaction solvent (and any components dissolved

therein) can be transferred from the first receptacle to the second receptacle, for example by opening a valve in a conduit extending between the first and second receptacles. Suitably, during said transfer the pressure in the first receptacle is reduced.

Preferably, the component of the reaction mixture which is least soluble in the reaction solvent and therefore predominantly separates is said catalyst. Thus, preferably, as the pressure in the first receptacle is reduced, for example by transferring reaction solvent to the second receptacle, catalyst precipitates in the first receptacle. Preferably, the reaction mixture (which suitably includes a relatively low level or substantially no catalyst) is received in said second receptacle wherein the pressure is P2. Then, the method may comprise reducing the pressure in the second receptacle so that a remaining component of the reaction mixture which is least soluble in the reaction solvent predominantly separates from the reaction mixture. The component of the reaction mixtures which separates may be a reactant or a product.

In said method, preferably, said second receptacle is connected to a third receptacle and the arrangement is such that reaction solvent (and any component dissolved therein) can be transferred from the second receptacle to the third receptacle. Suitably, during the transfer the pressure in said second receptacle is reduced from said pressure Pz.

The method may include subsequently reducing the pressure in the third receptacle so as to cause the precipitation of a remaining component therein to allow said remaining component to be isolated from the reaction solvent.

In some embodiments, unused reactant may be predominantly accumulated in one of the receptacles. These may be re- pressurised if necessary and returned to the first receptacle for use in a subsequent reaction.

Any feature of any aspect of any invention described herein may be combined with any feature of any aspect of any invention or embodiment described herein mutatis mutandis.

Specific embodiments of the invention will now be described, by way of example, with reference to the accompanying drawings, in which: Figure 1 is a schematic representation of apparatus for use in hydrogenation reactions; Figure 2 is a schematic representation of a collection vessel; Figure 3 is a graph of density of HFC 134a against pressure at 378K.

Figure 4 is a schematic representation of a separation system for separating catalyst, reagent and products from one another.

The following are referred to hereinafter: HFC 134a-refers to 1,1, 1,2-tetrafluoroethane.

Wilkinson's Catalyst (Ph3P) 3RhCl Structure: MR=925.24 Melting point: 245-250°C The catalyst is commercially available or may be prepared as described in Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G., J. Chem. Soc. A 1966, (12), 1711-32; Jardine, F. H.; Osborn, J. A.; Wilkinson, G. J. Chem. Soc.

A. 1996, (10), 1574-8; and Jardine, F. H.; Wilkinson, G. , J. Chem. Soc. C. 1967, (4), 270-1.

The high pressure apparatus, shown in figure 1, for use in hydrogenation reactions, comprises a reaction cell 40 having 3cm thick walls made from 316 stainless steel giving it a maximum working pressure of 1 kbar and being rated to 1.5 kbar. A high pressure seal between the body of the cell and the cell top is provided by a Teflon supported standard nitrile O-ring. The cell 40 is heated using a 240V, 250W band heater 42 supplied by Walton Ltd, U. K. Temperature is controlled and maintained (+0. 5K) using a CAL 9900 controller fitted with an iron/constantan thermocouple. The cell 40 is pressurised using an air driven hydraulic pump 44 supplied from air container 46,

via system air tap 47. Pressure is monitored (+2 bar) using a UCC type PGE 1001.600 manometer 48. The apparatus is fitted with bursting discs 50 and a pump isolation valve 51 for safety. Downstream of the cell 40 is a vent valve 41. Gaseous reaction medium is arranged to be supplied to the cell 40 from vessel 52 via gas tap 54.

Doser 56 is arranged to supply reagents to the cell 40.

The apparatus of figure 1 may be modified if special conditions are required for the catalyst used. For example, in asymmetric hydrogenation reactions catalysts which are air/moisture sensitive may be prepared in situ.

An example is Ru (II) -methylallyl [Cod] /BINAP/HX where X=Cl or Br. In this case, the doser 56 may be removed from the system and placed in a glove box where the pro/co- catalysts are loaded and sealed under nitrogen gas. The doser and its contents may then be replaced in the system.

A modified cell having an additional inlet for HX gas (required for in-situ catalytic species preparation) would need to be used so as to allow the EX gas to be introduced without allowing air or moisture into the cell. (Prior to the start of an experiment, air and moisture would be removed by flushing with solvent and/or hydrogen gas optionally with removal by a vacuum pump).

The apparatus shown in Figure 1 may generally be used as follows to carry out hydrogenation reactions. The top of the reaction cell 40 is fitted with an inlet (not shown) attached to a supply of hydrogen gas. The catalyst is placed into the cell 40 and the substrate is loaded into the doser 56. The cell 40 is heated to an appropriate temperature (that required for that particular experiment) and then charged with the required amount of hydrogen gas.

The cell is then pressurised by introducing reaction medium (e. g. HFC134a) into the cell, pumped from vessel 52 with the air-driven hydraulic pump 44. As it is pumped, the substrate is flushed from the doser 56 into the reaction cell. The reaction is left for the desired amount of time and then the products/unreacted starting materials are collected by depressurisation into a larger volume collection vessel 60 downstream of the cell 40, as shown in Figure 2. The collection vessel is constructed from 316 stainless-steel and has a much larger internal volume compared to the reaction cell (264 cm3 c. f. 30 cm3) so that venting from high pressures can be achieved safely. The trapping cell dimensions are 75 mm (height) and 60 mm (internal diameter) with a wall thickness of 6 mm. A restrictor tube 62, connecting trapping vessel to reaction cell 40, has a bore of 4 mm in diameter and is constructed from nylon tubing. The restrictor tube 62 is made as short as the experimental set up will allow in order to minimise precipitation of the product within the restrictor tube. The collection vessel 60 is vented though a pipe 64 (internal bore 4 mm i. d. ) into a fume cupboard exhaust. The products isolated in collection vessel 60 are analysed using NMR (ARX250), GC-MS (Perkin Elmer) and GC (UNICAM PU4500 capillary chromatograph) employing a SP4290 integrator (Spectra-Physics). GC was used to calculate the % conversion with respect to styrene converted to product.

Example 1-Solubility of Wilkinson's catalyst in HFC 134a A visual experiment was carried out using a high-pressure windowed cell (volume 7.5 cm3). The test showed that a 3 mMolar amount of Wilkinson's catalyst is soluble in supercritical HFC 134a at 105°C in the pressure range of

50-280 bar. This is more than adequate to justify the results obtained for the hydrogenation of styrene (shows a homogeneous phase catalyst and showed that over 10 times the amount of catalyst required could be solvated by this fluid).

Example Cl (comparative) -Solubility of Wilkinson's catalyst in supercritical carbon dioxide A visual experiment was carried out in a windowed high- pressure cell (volume of 7.5 cm3). The solubility of 0.0092g (1.33mMolar) of Wilkinson's catalyst in supercritical carbon dioxide was observed at 40°C in the pressure range 50-120 bar; none (or at least an unnoticeable amount) of the catalyst went into solution.

The apparatus described above with reference to Figure 1 was used to investigate the catalytic hydrogenation of styrene as described in Examples 2 to 4 below.

Example 2-Time Dependency of Reaction The doser 56 was loaded with styrene and Wilkinson's catalyst (2mg) (0.033 mol%) was placed directly into the cell 40. The cell was heated to 105°C and then charged with hydrogen gas (0.02 mols) from a gas cylinder having a cylinder pressure of 20 bar. The cell was then pressurised to 100 bar by introducing reaction medium HFC134a into it. As the reaction medium flows to the cell, it flushes styrene from the doser. At the pressure and temperature selected the HFC 134a is in a supercritical state.

The reaction in the cell was monitored periodically. In the reaction 0. 75cm3 of styrene was used initially. The reaction was repeated for different periods of time using the same conditions described. Results are provided in Table 1.

Table 1 Time (hours) % Conversion 1 76.5 2 82.9 3 85.9 4 87. 2 6 87. 5 8 86. 2 10 86. 7 From the results, it was concluded that the reaction had reached equilibrium after 2 hours and consequently subsequent styrene hydrogenation reactions were carried out for 2 hours (unless otherwise stated).

Example 3-Pressure Dependency Using the apparatus of figure 1, the effect of varying the pressure in the cell was investigated. In the example, the doser was loaded with styrene and Wilkinson's catalyst (2mg, 0.033 mol% with respect to styrene substrate) was placed directly in the cell. The cell was heated to 105°C and then charged with hydrogen gas (0.02 mol) at 20 bar (cylinder pressure). The cell was then pressurised by input of HFC134a from vessel 52 via doser 56 so that styrene is flushed into the cell thereby starting the reaction. The reaction was then allowed to proceed for 2 hours. A series of experiments were undertaken at

different cell pressures between 50 bar and 115 bar by varying the pressure of HFC134a. For all conditions, the HFC134a was in a supercritical state. 0. 75cm3 of styrene was used.

In the experiments two hydrogenation products were produced as illustrated by the following reaction / zizi - in 'i' Rh (PPh3) 3CI 6 6 styrene Major Minor (trace) The amounts of products were assessed using Gas Chromotography. However, only trace amounts of the minor product (ethylcyclohexane) were produced (except for the 100 bar pressure result which is regarded as ambiguous) and, accordingly, the GC peak was not integrated to determine actual amounts of the product. Results are provided in Table 2. The presence of the minor product was detected using mass spectroscopy.

Table 2 Pressure (bar) % Major % Minor 50 59.7 Trace 55 63.4 Trace 60 68.1 Trace 70 84.7 Trace 80 81.4 Trace 85 82.1 Trace 90 79.3 Trace 100 71. 2 11. 1 115 83. 6 Trace At HFC134a pressures lower than 70 bar the conversions are relatively low but increase with increasing pressure. At pressures of 70 bar and above the conversions do not show a pressure dependency as the pressure is increased. These results may be explained in terms of clustering (local density enhancement) around the reagent molecules. From Figure 3, it can be seen that density of HFC134a at 378K increases quite significantly between pressures of 40-70 bar but at 70 bar and above the density increase becomes less dramatic. This trend of change of solvent density with pressure may be related to the conversions of the hydrogenation pressure dependency.

Whilst Applicant does not intend to be bound by any theory, it is believed that at lower pressures the solvent clustering around the solute (substrate and catalyst) is only moderate but the local density will still be higher than that of the bulk solvent. This allows both hydrogen (which is in the supercritical state under these working

conditions; Tc = 33. 19 K, Pc = 13. 15 bar) to diffuse to [RhCl (PPh3) 3] to form the cis-dihydro complex [RhCl (H2) (PPh3) 2] and styrene to diffuse to the activated catalytic species and insert into the metal bond. As pressure is increased up to 70 bar, the clustering of both the solvent and hydrogen molecules around the catalyst increases, increasing the rate of dihydro complex formation. Although it is the attack of the olefin on the dihydro complex that is the rate-determining step, the reaction rate is enhanced due to the presence of more activated catalytic species.

At pressures above 70 bar the local density becomes closer to that of the bulk solvent and solvent clustering around the reagent is significant. The only way a reaction can now take place is by'desolvation' (solvent molecules diffusing away from the reagent) followed by solute-solute interactions. If it is assumed that this kinetic desolvation process occurs at a constant rate then the reaction rate will be governed by the thermodynamics of the rate-limiting step at elevated pressures.

Example 4-Transfer Hydrogenation As described in Example 3, hydrogenation of styrene (using H2 (g)) gave two products as per the reaction scheme above.

As an alternative, transfer hydrogenation reactions were carried out as a preliminary study to investigate if the minor product could be eliminated by using a molar ratio of substrate to hydrogen source of 1: 1. The hydrogen source selected was Et3N/HCOOH in a 5: 2 molar ratio ratio. Only the major product shown in example 3 was formed.

In the process Et3N/HCOOH and Wilkinson's catalyst were placed into the reaction vessel and the styrene was placed into the doser. The system was heated and pressurised as described in previous examples and the styrene was flushed into the reaction vessel upon pressurisation. The reaction was left to proceed for 2 hours after pressurisation and the results were obtained by GC analysis as described in previous examples. Identification of the product was carried out by mass spectroscopy.

In the reaction 2mg of catalyst and 0.75 cm3 of styrene were used. The % conversion for a range of pressures are provided in Table 3 below.

Table 3 Pressure (bar) % Conversion 60 1. 6 130 3. 1 180 3.5 215 3.9 Although the % conversion is low, no minor product was observed. It is believe that alternative catalyst, for example platinum or palladium catalyst, may be more effective than Wilkinson's catalyst used.

Example 5-Assymmetric hydrogenation in hydrofluorocarbon solvents The general procedure described above was used to investigate hydrogenation of two alternative substrates (1 and 2 shown below) and two alternative catalysts (3 and 4 shown below). 0 COOMB 0 COOMB 1 2 [ (cod) Rh (josphos)] BF 4 (OAc) 2Ru (binap) 3 4 Additionally, the solvents used were difluoromethane and 50: 50 mixtures of carbon dioxide and 1,1, 1,2- tetrafluoroethane.

In a typical experiment, the reaction cell was charged with a tetrahydrofuran (THF) solution of the catalyst.

Such a solution was used to make measurement easier since the milligram quantities of catalyst used are difficult to measure out. The THF was removed under vacuum before the hydrogenation reaction so that the THF does not interfere with the reaction. The cell was heated to the desired temperature and pressurised with hydrogen. The substrate (1-2 mmol) was put in the doser and added to the reaction mixture by pumping the hydrofluorocarbon through the doser at the appropriate pressure. After stirring the reaction mixture for 2-64 hours, the cell was depressurised and the content was trapped in a cold trap which was cooled with liquid nitrogen. The cold trap was then slowly warmed to room temperature. The contents of the cold trap and reaction cell were combined and dissolved in chloroform.

The solution was analysed by GC and NMR spectroscopy.

Details of reagents used, conditions selected and results are provided in Table 4 below for experiments A-0. In the table 134a refers to 1,1, 1,2-tetrafluoroethane ;"cat" <BR> <BR> <BR> <BR> refers to the catalyst ; "cat mol%"refers to the mole% of catalyst relative to that of the substrate ;"p of H2/bar" refers to the pressure in bars of hydrogen pumped into the reaction cell ;"p/bar"refers to the total pressure in bars in the reaction cell ;"T/°C"refers to the temperature in the reactor;"conv."refers to the percentage of substrate converted to the hydrogenation product; and"enantios"refers to the enantiomer excess (%) of one enantiomer of the product relative to the other enantiomer.

Table 4 Exp solvent subs cat cat p of p/T/° Time/h conv. enan . trat mol% H2/bar C tios e bar A CO2/ 134a 1 4 0.1 4 200 70 3 2 B C02/134a 1 4 0. 2 20 200 70 24. 5 4 C CH2F2 2 4 0. 2 20 200 90 18 51 D CH2F2 2 4 0. 2 20 190 90 64 98 E CH2F2 2 4 0. 4 20 190 90 18 90 F CH2F2 2 4 0. 1 20 280 90 16. 5 55 G CH2F2 2 4 0. 2 20 205 90 16. 5 59 H CH2F2 1 3 0.1 20 200 90 18 11 2 I CH2F2 1 3 0. 4 20 190 90 15. 5 72 5 J CH2F2 1 3 0. 8 20 200 90 16 99 63 K CH2F2 2 3 0. 2 20 200 90 16 >99 L CO2/ 134a 1 3 0.4 10 245 70 16 43 10 M CO2/ 134a 1 3 0.3 20 260 90 17.5 82 2 N CO2/ 134a 1 3 0.4 20 230 70 16 78 O C02/134a 1 3 0. 4 20 270 90 16 41

Example 6-Hydrogenation of styrene in 1,1, 1,2, 3,3, 3, - Heptafluoropropane (HFC 227ea) The reaction was carried out generally as described above, except that HFC 227ea was used instead of HFC134a. In this regard, 0.75 mL of styrene was placed into the doser and 3mg of Wilkinson's catalyst was placed into the reaction cell. The cell was heated to 105°C and charged with 30 bar of hydrogen gas. The cell was then pressurised with HFC 227ea giving a total pressure of 60 bar in the reactor. During pressurisation the styrene was flushed from the doser into the reaction cell by the solvent gas. The reaction was carried out for varying time lengths and the % conversion was measured using GC.

Results are provided in the table below. The time dependency of the reaction is illustrated in figure 5. Time (hours) % Conversion 1. 0 73. 6 2. 0 75. 2 3. 0 76. 6 5. 5 78. 3 8. 5 100. 0 Example 7 A catalyst system was prepared in accordance with the description below.

Catalyst system 1: Monophos/Rh (COD) 2BF4 p Rh [(L) 2 (COD)] BF4

"Monophos"is 2, 2-0, 0- (1, 1-Binaphthyl)-O, O-dioxo-N, N- dimethylphospholidine (a)"Monophos"ligand preparation I I I I / H /O/ OH + P (NMe2) 3 >, P-N OH Binol R/S HPMT R/S Monophos 1, 1-Bi (2 naphthol) Hexamethylphosphorous triamide MR = 286. 33 MR= 163. 21 MR = 359. 36 d = 0. 898g/cm3 (b) Catalyst preparation 2.010g of Binol dissolved in approx. 20mL of ether and 1. 6mL HPMT added. Mixture stirred at room temperature for 2.5 hours. Product filtered and washed with hexane giving 2.298g of ligand product (91% yield). All preparation carried out using standard Shlenk techniques.

The ligand purity was tested using NMR (1H, 31P, 13C), polarimetry and melting point testing. The data obtained was compared to the literature and the ligand was found to be pure and suitable for catalysis.

Purity data: R Monophos tap =-570° m. p. = 218-220°C S Monophos [α]D20= +569°

m. p. = 215-217°C The catalyst system was tested for validity using conventional solvents and was found to be valid. It was then used to carry out the asymmetric hydrogenation of itaconic acid (Methylenesuccininc acid) in supercritical HFC134a with 1. 21x10-3 moles of H2 (g) at 110°C. Pressure conditions, length of reaction and results are given in the table below. HOOC Ho COOH HOOC COOH monophos/RH catalyst Itaconic acid Methylsuccinic acid (c) Method of Hydrogenation The cell was heated to 110°C. 26mg of itaconic acid, 4mg of Rh (COD) 2BF4 and 8mg of (R) -monophos were weighed out in a dry box under a nitrogen atmosphere. These compounds were transferred under a nitrogen atmosphere to the high pressure cell and the air in the cell was replaced with 1.3 bar (equivalent to 1. 21x10-3 moles of H2) of H2 (g). The HFC 134a was charged to the pressures shown in the table below. When the required time had elapsed the cell was depressurised and the compounds were collected by dissolution in an appropriate solvent. Conversion was determined by NMR and GC. Enantiomeric excess (% ee) was determined with a Chireldex B-DM column using GC. % Ee is reported with respect to the (R) -methylsuccinic acid product.

Results Time Pressure % Conversion % ee (hours) (bar) 2 120 24 54. 5 21451547. 4 Table-Results for the asymmetric hydrogenation of itaconic acid using the (R) -Monophos/Rh catalyst system.

Example 8-In situ separation The solubilities of reagents, products and catalysts in the supercritical reaction media can be controlled easily and predictably by altering pressure. This property can be exploited to effect in situ separation after hydrogenation. Furthermore, the separation may be carried out with the reagents, products and catalyst in the reaction vessel.

Apparatus for carrying out in situ separation is shown in Figure 4. It should be noted that vessels/pipework upstream of vessel 2 for effecting a hydrogenation reaction have been omitted but that vessel 2 in figure 4 is the same as vessel 40 in figure 1. Referring to figure 4, reactor vessel 2 is connected via pipe 4 to vessel 6 which in turn is connected via pipe 8 to vessel 10. Flow of fluids in pipes 4 and 8 is controlled by respective taps 12,14 which are placed as close as possible to the vessel outlets to reduce the risk of products precipitating in the pipes. A reagent re-cycling pipe 16 is connected between the vessels 6 and 2. Also, vessel 10 includes a vent/gas recycle pipe 18, the flow to which is controlled by tap 20.

After a high pressure reaction (e. g. at 180-200 bar) has been completed in vessel 2, tap 12 is opened and vessel 2 is depressurised to a pressure of 100-120 bar which facilitates precipitation of the catalyst into vessel 2 (on the basis that the catalyst has the lowest solubility in the solvent). The reagents and products (which have greater solubility in the solvent) will remain in solution in the solvent and be carried into vessel 6. If for example the reagent has lower solubility in the solvent than the product then, on opening tap 14, the reagent will be precipitated in vessel 6 and the product will be carried in solution into vessel 10. Optionally, the reagent may be returned to vessel 2 via pipe 16 for use in a subsequent reaction.

The separation system may be illustrated by a study of itaconic acid (unsaturated substrate) and methylsuccinic acid (hydrogenation product). Tables 5 and 6 detail the solubility in HFC134a at 378K of itaconic acid and methylsuccinic acid at various pressures.

Table 5 Itaconic acid Pressure (bar) Solubility (mol dom-3) 50 0. 01593 80 0.01819 105 0.02151 140 0.02203 180 0.02259 Table 6 Methylsuccinic Acid Pressure (bar) Solubility (mol dm-3) 48 0. 01637 70 0.01888 90 0.02239 110 0.06425 140 0.07857 200 0. 08038 Thus, it will be appreciated that for a hydrogenation reaction of itaconic acid, the substrate and product could be separated using the methodology described with reference to Figure 4 and, furthermore, provided the catalyst has lower solubility then both the substrate and product, the catalyst can also be separated (by it remaining in vessel 2).

Thus, by selection of catalyst, substrates, solvents and working conditions, hydrogenation reactions can be undertaken and products can be isolated efficiently and effectively.

The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

The invention is not restricted to the details of the foregoing embodiment (s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.